In patients with ARDS, identification of the critical mechanisms and the testing of targeted interventions have been hampered by the practical difficulties inherent in the study of critically-ill patients. As stated in the original proposal Project One, such problems could be alleviated if a "human model" existed in which appropriate samples and physiologic- clinical data could be obtained prior to the onset. At that time, we indicated that such a model appeared to exist; namely; patients with chronic major vessel thromboembolic pulmonary hypertension (CT-E PH) in whom post-operative "reperfusion edema" appeared routinely and in whom preliminary observation disclosed that this was a high-permeability edema. We proposed, at that time, to study these patients sequentially with physiologic and radiographic technic and samples of blood and broncho-alveolar lavage fluid to seek evidence for such phenomena as release of neutrophil products, oxygen metabolites, cytokines; and abnormalities of surfactant function or composition. It was our postulate that, if this human model could be further validated, study of such patients would allow us to identify critical mediators of acute lung injury, the course of the injury, and, in this population, initiate pilot interventions targeted against specific perturbations. With such insights and pilot trials, the population with, or at risk of ARDS could then be addressed. A substantial body of data now has been generated validating that these patients do develop, consistently, an acute lung injury in the post- operative period which closely parallels, biochemically, clinically and physiologically, ARDS. Further, a pilot intervention study has been initiated employing a specific inhibitor of human neutrophil elastase. We plan to continue the sequential study of these patients to further characterize the potential mediators and course of the acute lung injury. The pilot study of the HNE-inhibitor also will continue. Relevant animal models also will be studied. Further, as preliminary animal and human investigations reach a mature stage, the use of inhaled nitric oxide (NO) will be explored in these patients and in animal models. Nitric oxide appears to have particularly favorable characteristics as the next logical intervention in patients with acute lung injury. As successful and safe 'targeted' therapeutic/preventive initiatives evolve from such investigations, they will be applied to patients with, or at risk of, ARDS.